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Jolijn R van Leeuwen,1 Luca Quartuccio,2 Juliana Bordignon Draibe,3 Iva Gunnarson,4 Ben Sprangers,5 Y K Onno Teng1 1Center of Expertise for Lupus-, Vasculitis- and Complement-Mediated Systemic Diseases (Luvacs), Department of Internal Medicine - Nephrology Section, Leiden University Medical Center, Leiden, the Netherlands; 2Division of Rheumatology, Department of Medicine, University of Udine, Udine, Italy; 3Department of Nephrology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain; 4Division of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Karolinska University Hospital, Stockholm, Sweden; 5Department of Nephrology, Ziekenhuis Oost Limburg Genk, Genk, BelgiumCorrespondence: Y K Onno Teng, Department of Nephrology, Leiden University Medical Center (LUMC), P.O. Box 9600, Leiden, 2300 RC, the Netherlands, Tel +31-71-5262148, Fax +31-71-5266868, Email Y.K.O.Teng@lumc.nlAbstract: Recently, avacopan has been approved for the treatment of ANCA-associated vasculitis (AAV). Avacopan is an inhibitor of the C5a-receptor, which plays an important role in chemotaxis and the amplification loop of inflammation in AAV. In the most recent, international guidelines avacopan is recommended as steroid-sparing agents for the management of AAV. Here, we review the clinical trials that have led to demonstrate that avacopan is an effective treatment option in the management of AAV, where it can significantly reduce the cumulative dosage of glucocorticoids (GC). Despite the new guideline recommendations, clear guidance on how to employ avacopan in real-world clinical practice is lacking. We therefore also address in this review the data and clinical experience with avacopan obtained from real-world evidence. Combining preclinical studies, clinical trials, and real-world evidence helps to provide a better position of avacopan for the management of AAV in routine clinical practice, taking advantage of the GC-sparing effects of avacopan as a possible solution for the current challenge of reducing GC-toxicity in AAV patients. Furthermore, we delineate current knowledge gaps and future research areas that need to be addressed.Keywords: antineutrophil cytoplasmic antibody, ANCA, pauci-immune glomerulonephritis, complement, C5a inhibition, glucocorticoid toxicity

Jolijn R van Leeuwen,1,* Tamara Popov,2,* Achim Obergfell,2 Ton J Rabelink,1 YK Onno Teng1 1Center of Expertise for Lupus-, Vasculitis- and Complement-Mediated Systemic Diseases (LuVaCs), Department of Internal Medicine - Nephrology Section, Leiden University Medical Center, Leiden, the Netherlands; 2Vifor Pharma Ltd, Glattbrugg, Switzerland*These authors contributed equally to this workCorrespondence: YK Onno Teng, Department of Nephrology, Leiden University Medical Center (LUMC), P.O. Box 9600, 2300 RC, Leiden, the Netherlands, Tel +31-071-5262148, Fax +31-071-5266868, Email Y.K.O.Teng@lumc.nl

Background: Because anti-neutrophil cytoplasmatic antibody (ANCA)-associated vasculitis (AAV) is a rare, life-threatening, auto-immune disease, conducting research is difficult but essential. A long-lasting challenge is to identify rare AAV patients within the electronic-health-record (EHR)-system to facilitate real-world research. Artificial intelligence (AI)-search tools using natural language processing (NLP) for text-mining are increasingly postulated as a solution., Methods: We employed an AI-tool that combined text-mining with NLP-based exclusion, to accurately identify rare AAV patients within large EHR-systems (>2.000.000 records). We developed an identification method in an academic center with an established AAV-training set (n = 203) and validated the method in a non-academic center with an AAV-validation set (n = 84). To assess accuracy anonymized patient records were manually reviewed., Results: Based on an iterative process, a text-mining search was developed on disease description, laboratory measurements, medication and specialisms. In the training center, 608 patients were identified with a sensitivity of 97.0 % (95%CI [93.7, 98.9]) and positive predictive value (PPV) of 56.9 % (95%CI [52.9, 60.1]). NLP-based exclusion resulted in 444 patients increasing PPV to 77.9 % (95%CI [73.7, 81.7]) while sensitivity remained 96.3 % (95%CI [93.8, 98.0]). In the validation center, text-mining identified 333 patients (sensitivity 97.6 % (95%CI [91.6, 99.7]), PPV 58.2 % (95%CI [52.8, 63.6])) and NLP-based exclusion resulted in 223 patients, increasing PPV to 86.1 % (95%CI [80.9, 90.4]) with 98.0 % (95%CI [94.9, 99.4]) sensitivity. Our identification method outperformed ICD-10-coding predominantly in identifying MPO+ and organ-limited AAV patients., Conclusions: Our study highlights the advantages of implementing AI, notably NLP, to accurately identify rare AAV patients within large EHR-systems and demonstrates the applicability and transportability. Therefore, this method can reduce efforts to identify AAV patients and accelerate real-world research, while avoiding bias by ICD-10-coding., Competing Interests: Declaration of competing interest The work of YKOT is supported by the Dutch Kidney Foundation (17OKG04) and by the Arthritis Research and Collaboration Hub (ARCH) foundation. ARCH is funded by Dutch Arthritis Foundation (ReumaNederland). YKOT received an unrestricted research grant from GlaxoSmithKline, Aurinia Pharmaceuticals and Vifor Pharma. The LUMC received consulting fees from Aurinia Pharmaceuticals, Novartis, GSK, KezarBio, Vifor Pharma, Otsuka Pharmaceuticals on consultancies delivered by YKOT., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: The work of Y.K.O.T. is supported by the Dutch Kidney Foundation (17OKG04) and by the Arthritis Research and Collaboration Hub (ARCH) foundation. ARCH is funded by the Dutch Arthritis Foundation (ReumaNederland). Y.K.O.T. received an unrestricted research grant from GlaxoSmithKline, Aurinia Pharmaceuticals, and Vifor Pharma. The LUMC received consulting fees from Aurinia Pharmaceuticals, Novartis, GSK, KezarBio, Vifor Pharma, Otsuka Pharmaceuticals on consultancies delivered by Y.K.O.T. D.W. is supported by a FOREUM career grant.

Introduction: Both rituximab (RTX) and cyclophosphamide (CYC) are effectively used in combination with steroids as remission induction therapy for patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Several studies have shown that the effect on achieving (clinical) remission, frequency and severity of relapses is equivalent for both therapies, but there is accumulating data that the long-term safety profile of RTX might outperform CYC. Combination of RTX with low-dose CYC (LD-CYC) has been investigated in only a few uncontrolled cohort studies, in which clinical remission and a favourable immunological state with low relapse rates was quickly achieved. In this randomised controlled trial, we aim to investigate whether the combination treatment (RTX+LD CYC) is superior in comparison to standard care with RTX only., Methods and Analysis: This study is an open-label, multicentre, 1:1 randomised, prospective study for patients with AAV with generalised disease, defined as involvement of major organs, that is, kidneys, lungs, heart and nervous system. In total, 100 patients will be randomised 1:1 to receive either remission induction therapy with standard of care (RTX) or combination treatment (RTX+LD CYC) in addition to steroids and both arms are followed by maintenance with RTX retreatments (tailored to B-cell and ANCA status). Our primary outcome is the number of retreatments needed to maintain clinical remission over 2 years. Secondary outcomes are relevant clinical endpoints, safety, quality of life and immunological responses., Ethics and Dissemination: This study has received approval of the Medical Ethics Committee of the Leiden University Medical Center (P18.216, NL67515.058.18, date: 7 March 2019). The results of this trial (positive and negative) will be submitted for publication in relevant peer-reviewed publications and the key findings presented at national and international conferences., Trial Registration Number: NCT03942887., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A reflex hammer for measurement of the mechanical stimulus strength was designed. Combined with standard EMG equipment this instrument permits the study of both stimulus-response relations and latencies of myotatic reflexes. Some results in normal subjects are discussed.